Vitamin D receptor promotes healthy microbial metabolites and microbiome

Chatterjee, Ishita; Lü, Rong; Zhang, Yongguo; Zhang, Jilei; Dai, Yang; Xia, Yinglin; Sun, Jun

doi:10.1038/s41598-020-64226-7

Cited by 54 publications

(57 citation statements)

References 47 publications

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“…37 Conditional VDR deletion severely changed metabolites specifically produced from carbohydrate, protein, lipid, and bile acid metabolism. 37 In the future, we will study VDR in immune cells during cancer development.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor Protects Against Dysbiosis and Tumorigenesis via the JAK/STAT Pathway in Intestine

Zhang

Lü

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Vitamin D/vitamin D receptor (VDR) deficiency causes a high risk of colon cancer, but how VDR is involved in tumorigenesis through microbiota remains unknown. We provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis, indicating a new target: microbiome and VDR for the prevention of cancer. BACKGROUND & AIMS: Vitamin D exerts regulatory roles via vitamin D receptor (VDR) in mucosal immunity, host defense, and inflammation involving host factors and microbiome. Human Vdr gene variation shapes the microbiome and VDR deletion leads to dysbiosis. Low VDR expression and diminished vitamin D/VDR signaling are observed in colon cancer. Nevertheless, how intestinal epithelial VDR is involved in tumorigenesis through gut microbiota remains unknown. We hypothesized that intestinal VDR protects mice against dysbiosis via modulating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in tumorigenesis. METHODS: To test our hypothesis, we used an azoxymethane/ dextran sulfate sodium-induced cancer model in intestinal VDR conditional knockout (VDR DIEC) mice, cell cultures, stem cell-derived colonoids, and human colon cancer samples. RESULTS: VDR DIEC mice have higher numbers of tumors, with the location shifted from the distal to proximal colon. Fecal microbiota analysis showed that VDR deletion leads to a bacterial profile shift from normal to susceptible carcinogenesis. We found enhanced bacterial staining in mouse and human tumors. Microbial metabolites from VDR DIEC mice showed increased secondary bile acids, consistent with observations in human CRC. We further identified that VDR protein bound to the Jak2 promoter, suggesting that VDR transcriptionally regulated Jak2. The JAK/ STAT pathway is critical in intestinal and microbial homeostasis. Fecal samples from VDR DIEC mice activate the STAT3 signaling in human and mouse organoids. Lack of VDR led to hyperfunction of Jak2 in response to intestinal dysbiosis. A JAK/STAT inhibitor abolished the microbiome-induced activation of STAT3. CONCLUSIONS: We provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis. It indicates a new target: microbiome and VDR for the prevention of cancer.

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Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor Protects Against Dysbiosis and Tumorigenesis via the JAK/STAT Pathway in Intestine

Zhang

Lü

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…It may be further implicated in the GMB axis of neurologic disorders. Deletion of intestinal epithelial VDR increased kynurenine, a pathway associated with inflammatory neurological disorder in a mouse model [ 144 ]. Our recent study has also shown that the mice with VDR deletion in immune cells displayed significant downregulation of quinolinate and tocopherol pathway-derived metabolites and increase in nicotinamide.…”

Section: Microbial Metabolite In Autism Spectrum Disorder and Attentimentioning

confidence: 99%

“…These changes indicate a potential role of VDR in neurophysiology. The role of vitamin D/VDR in gut–brain axis needs further investigation in future research [ 144 ].…”

Section: Microbial Metabolite In Autism Spectrum Disorder and Attentimentioning

confidence: 99%

Gut instincts: vitamin D/vitamin D receptor and microbiome in neurodevelopment disorders

2020

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The gut microbiome regulates a relationship with the brain known as the gut–microbiota–brain (GMB) axis. This interaction is influenced by immune cells, microbial metabolites and neurotransmitters. Recent findings show gut dysbiosis is prevalent in autism spectrum disorder (ASD) as well as attention deficit hyperactivity disorder (ADHD). There are previously established negative correlations among vitamin D, vitamin D receptor (VDR) levels and severity of ASD as well as ADHD. Both vitamin D and VDR are known to regulate homeostasis in the brain and the intestinal microbiome. This review summarizes the growing relationship between vitamin D/VDR signalling and the GMB axis in ASD and ADHD. We focus on current publications and summarize the progress of GMB in neurodevelopmental disorders, describe effects and mechanisms of vitamin D/VDR in regulating the microbiome and synoptically highlight the potential applications of targeting vitamin D/VDR signalling in neurodevelopment disorders.

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“…There is also evidence that probiotics play a role in these modulations. Our recent study has shown that VDR promotes healthy microbial metabolites and microbiome in a tissue specific and gender specific manner [149]. However, more studies are necessary to elucidate this influence and all the metabolic steps associated.…”

Section: Probiotic Role Regulated By Vitamin D/vdrmentioning

confidence: 98%

“…In addition to microbiome regulation, long chain acylcarnitines (LCACs), tocopherol, and equol metabolisms were also influenced by VDR function and HFD. Thus, it can be concluded that both, diet and VDR status, play a role in metabolic diseases, inflammation, risk of colon cancer, and epigenetic pathways [149].…”

Section: Probiotic Role Regulated By Vitamin D/vdrmentioning

confidence: 99%

Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

Battistini¹,

Ballan²,

Herkenhoff³

et al. 2020

Preprint

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Inflammatory bowel disease (IBD) is a chronic disease in the gastrointestinal tract (GIT). IBD include ulcerative colitis (UC), which generally affects only the large intestine mucosa and submucosa, and Crohn’s disease (CD), which may affect any part of the GIT by transmural inflammation. Both UC and CD are associated with an imbalance of the gut microbiota composition and injuries in the intestinal mucosa. The intestinal dysbiosis is related to a reduction in butyrate-producing species, impairing the anti-inflammatory response of the immune system, and is commonly associated with micronutrients deficiency, e.g. vitamin D hypovitaminosis. Vitamin D is involved in several critical functions, including immune cell differentiation, regulation of microbiota, gene transcription, and barrier integrity. Vitamin D supplementation in IBD patients showed promising results in reducing the disease activity and modulating gut microbiota. Vitamin D receptor (VDR) regulates the biological actions of the active vitamin D metabolite, 1α,25-dihydroxyvitamin D3. Evidence supports that the VDR signaling is involved in the genetic, environmental, immune, and microbial aspects of IBD. Low VDR expression and dysfunction of vitamin D/VDR signaling are reported in IBD patients. Vitamin D/VDR deficiency could be considered as a multifunctional susceptibility factor in IBD. Therefore, in this review, we will discuss the progress in clinical studies, mechanism studies on Vitamin D /VDR, and potential use of vitamin D supplementation as adjuvant therapy to restore gut microbiota balance, promote beneficial metabolites, and inhibit inflammation status in patients with IBD.

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Vitamin D receptor promotes healthy microbial metabolites and microbiome

Cited by 54 publications

References 47 publications

Vitamin D Receptor Protects Against Dysbiosis and Tumorigenesis via the JAK/STAT Pathway in Intestine

Vitamin D Receptor Protects Against Dysbiosis and Tumorigenesis via the JAK/STAT Pathway in Intestine

Gut instincts: vitamin D/vitamin D receptor and microbiome in neurodevelopment disorders

Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

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